18-48948427-G-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_005904.4(SMAD7):c.624C>A(p.Pro208=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00194 in 1,595,350 control chromosomes in the GnomAD database, including 43 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. P208P) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.0017 (5 hom., cov: 32)
  • Exomes 𝑓: 0.0020 (38 hom.)
• Consequence: SMAD7 NM_005904.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.412

Genes affected

SMAD7 (HGNC:6773): (SMAD family member 7) The protein encoded by this gene is a nuclear protein that binds the E3 ubiquitin ligase SMURF2. Upon binding, this complex translocates to the cytoplasm, where it interacts with TGF-beta receptor type-1 (TGFBR1), leading to the degradation of both the encoded protein and TGFBR1. Expression of this gene is induced by TGFBR1. Variations in this gene are a cause of susceptibility to colorectal cancer type 3 (CRCS3). Several transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jun 2010]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.73).
• BP6: Variant 18-48948427-G-T is Benign according to our data. Variant chr18-48948427-G-T is described in ClinVar as [Benign]. Clinvar id is 713314.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.412 with no splicing effect.
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.0017 (259/152352) while in subpopulation EAS AF= 0.0276 (143/5190). AF 95% confidence interval is 0.0239. There are 5 homozygotes in gnomad4. There are 145 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd at 261 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SMAD7	NM_005904.4	c.624C>A	p.Pro208=	synonymous_variant	2/4	ENST00000262158.8
SMAD7	NM_001190821.2	c.624C>A	p.Pro208=	synonymous_variant	2/4
SMAD7	NM_001190822.2	c.-22C>A		5_prime_UTR_variant	2/4
SMAD7	XM_047437509.1	c.-22C>A		5_prime_UTR_variant	2/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SMAD7	ENST00000262158.8	c.624C>A	p.Pro208=	synonymous_variant	2/4	1	NM_005904.4	P4
SMAD7	ENST00000589634.1	c.624C>A	p.Pro208=	synonymous_variant	2/4	4		A1
SMAD7	ENST00000586093.1	c.-22C>A		5_prime_UTR_variant	1/3	2
SMAD7	ENST00000591805.5	c.-22C>A		5_prime_UTR_variant	2/4	2

Frequencies

GnomAD3 genomes AF: 0.00171 AC: 261 AN: 152234 Hom.: 5 Cov.: 32

Gnomad AFR AF: 0.000579

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00111

Gnomad ASJ AF: 0.00634

Gnomad EAS AF: 0.0279

Gnomad SAS AF: 0.00186

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000588

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.00299 AC: 702 AN: 234504 Hom.: 7 AF XY: 0.00283 AC XY: 360 AN XY: 127280

Gnomad AFR exome AF: 0.000398

Gnomad AMR exome AF: 0.00173

Gnomad ASJ exome AF: 0.00768

Gnomad EAS exome AF: 0.0268

Gnomad SAS exome AF: 0.00167

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000639

Gnomad OTH exome AF: 0.00194

GnomAD4 exome AF: 0.00197 AC: 2837 AN: 1442998 Hom.: 38 Cov.: 28 AF XY: 0.00195 AC XY: 1398 AN XY: 717912

Gnomad4 AFR exome AF: 0.000909

Gnomad4 AMR exome AF: 0.00186

Gnomad4 ASJ exome AF: 0.00692

Gnomad4 EAS exome AF: 0.0414

Gnomad4 SAS exome AF: 0.00161

Gnomad4 FIN exome AF: 0.0000188

Gnomad4 NFE exome AF: 0.000600

Gnomad4 OTH exome AF: 0.00208

GnomAD4 genome AF: 0.00170 AC: 259 AN: 152352 Hom.: 5 Cov.: 32 AF XY: 0.00195 AC XY: 145 AN XY: 74506

Gnomad4 AFR AF: 0.000577

Gnomad4 AMR AF: 0.00111

Gnomad4 ASJ AF: 0.00634

Gnomad4 EAS AF: 0.0276

Gnomad4 SAS AF: 0.00186

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000588

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.00104 Hom.: 1

Bravo AF: 0.00213

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Dec 31, 2019

- -

SMAD7-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

May 22, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.73
Cadd	Benign	5.7
Dann	Benign	0.66

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs145686330; hg19: chr18-46474797; COSMIC: COSV50989642;